EP1124631A2 - Verfahren zum binden von bio-molekülen an einer probestelle - Google Patents

Verfahren zum binden von bio-molekülen an einer probestelle

Info

Publication number
EP1124631A2
EP1124631A2 EP99953162A EP99953162A EP1124631A2 EP 1124631 A2 EP1124631 A2 EP 1124631A2 EP 99953162 A EP99953162 A EP 99953162A EP 99953162 A EP99953162 A EP 99953162A EP 1124631 A2 EP1124631 A2 EP 1124631A2
Authority
EP
European Patent Office
Prior art keywords
test site
molecules
bonding material
providing
light
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP99953162A
Other languages
English (en)
French (fr)
Other versions
EP1124631B1 (de
Inventor
Barbara Foley
Natalia Briones
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cytiva Sweden AB
Original Assignee
Amersham Bioscience AB
Motorola Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amersham Bioscience AB, Motorola Inc filed Critical Amersham Bioscience AB
Publication of EP1124631A2 publication Critical patent/EP1124631A2/de
Application granted granted Critical
Publication of EP1124631B1 publication Critical patent/EP1124631B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
    • G01N33/553—Metal or metal coated
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00427—Means for dispensing and evacuation of reagents using masks
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/0063—Other, e.g. van der Waals forces, hydrogen bonding
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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    • B01J2219/00632—Introduction of reactive groups to the surface
    • B01J2219/00637—Introduction of reactive groups to the surface by coating it with another layer
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00646—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
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    • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
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    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

  • This invention relates to fabrication of bio-molecule analyzers .
  • the present invention relates to methods of bonding, i.e. fixing or attaching physically but not necessarily chemically, bio-molecules to test sites .
  • probe molecules to the test sites includes polymerization of monomers attached to the probe molecule. While effective, the bond can be tenuous. Thus a new and novel method of bonding is desired, which provides robust and uniform deposition of the bio-molecule probes.
  • Another object of the present invention is to provide a method of bonding probe molecules to test sites which is robust and uniform.
  • a method of bonding bio- molecules to a test site including providing a substrate having a test site defined on a surface thereof, providing a solution containing a plurality of probe molecules and bonding material, directing light from a light source onto the test site so as to cause the bonding material to bond the probe molecules to the test site.
  • the bonding material includes a binder which cross-links under the influence of the light, capturing and retaining the bio-molecules.
  • a further specific method of bonding includes providing a test site having a metal base, directing the light onto the metal base so as to heat the metal base, and providing a bonding material, bonded to the bio- molecules, which melts in response to the heat of the metal base and adheres to the test site.
  • FIG. 1 is a sectional view of a bio-molecule analyzer according to the present invention
  • FIG. 2 is a sectional view illustrating another embodiment of a bio-molecule analyzer according to the present invention
  • FIG. 3 is a greatly enlarged sectional view illustrating a method of bonding bio-molecules to a test site according to the present invention.
  • FIGS. 4 is a greatly enlarged sectional view illustrating another method of bonding bio-molecules to a test site according to the present invention.
  • Bio-molecule analyzer 10 includes a substrate 12 preferably fabricated of silicon, glass, plastic, etc., a thin conductive layer 14 formed on substrate 12, and a photoconductive layer 16 formed on thin conductive layer 14.
  • Thin conductive layer 14 can be any conductive material such as gold, platinum etc., and can be indium tin oxide (ITO) or other optically transparent conductors for reasons which will become apparent from the subsequent description.
  • Photoconductive layer 16 is a material such as amorphous silicon, CdS, CdSe, various photoconductive polymers, etc. which becomes conductive when subjected to light.
  • a lead 18 is coupled to conductive layer 14 and a lead 20 is coupled to a solution 22 positioned in electrical contact , ith a surface 24 of photoconductive layer 16 opposite to conductive layer 14.
  • solution 22 is in electrical contact only with surface 24 " and not with conductive layer 14.
  • a potential is applied across leads 18 and 20 and thus between solution 22 and conductive layer 14.
  • test sites 30 are directed through a portion 34 of photoconductive layer 16 defining a test site 30 (preferably one test site for each beam) .
  • test sites 30 are formed into an array, with each test site 30 being an area of surface 24 substantially coextensive with a corresponding portion 34.
  • the beam or beams of light 33 complete an electrical circuit between conductive layer 14 and solution 22 through portion 34 of photoconductive layer 16. This is accomplished by beam of light 33 temporarily converting portion 34 of photoconductive layer 16 to a conducting medium.
  • Solution 22 contains ionic probe molecule to be bound to test sites 30. By completing the circuit, the ionic probe molecules in solution 22 are attracted to and concentrate proximate surface 24 at a selected one or ones of test sites 30.
  • any method of controllably illuminating a selected portion 34 of photoconductive layer 16 can be used, such as a masked light source, the use of a laser or diode array 35 or similar device instead of or in combination with a mask which permits passage of light in only the desired locations.
  • Array 35 can be a one dimensional or two dimensional array of light sources which are individually addressable, i.e. one or more light sources can be activated as desired.
  • the array of test sites 30 (micro-locations) defined on surface 24 have groups of probes 32 coupled thereto.
  • Each test site 30 contains a plurality of probes 32 which are capable of binding to specific molecular structures.
  • the molecular structure can comprise, for example, bio- molecules such as polynucleotides, protein, DNA, RNA, enzymes, antibodies, antigens, etc.
  • probes 32 can comprise, for example, oligonucleotides . All probes 32 at a given test site 30 are identical. Probes in respective test sites differ in sequence for simultaneous detection of a plurality of different target molecules within a single array.
  • Each test site 30 is individually addressable by array 35 to provide the ability to attract ionic probe molecules from solution 22 to selected test site(s) 30 in order to fabricate an array of test sites each for detecting different molecules or sequences.
  • light 33 is directed at photoconductive layer 16 through solution 22.
  • substrate 12 must be formed of a material transparent to light 33 such as glass, plastic, etc.
  • thin conductive layer 14 must be a transparent conductor such as indium tin oxide (ITO) , various thin metals or other optically transparent materials.
  • ITO indium tin oxide
  • a specific process of fabricating a bio-molecule analyzer includes providing a first solution, containing a plurality of first probe molecules, in electrical contact with the plurality of test sites 30.
  • An electrical potential is applied between the first solution and the layer of electrically conductive material 14 by means of leads 18 and 20.
  • a beam of light 33 is directed through a first portion 34 of the photoconductive layer 16 to complete an electrical circuit between the layer of electrically conductive material 14 and the first solution through the first portion 34 of the photoconductive layer 16 and a first test site 30 of the array of test sites. Completing the electrical circuit causes first probe molecules in the first solution to be attracted to a first test site 30.
  • the first solution contains bonding material along with the first probe molecules.
  • Beam of light 33 from the light source is contemporaneously directed onto the first test site so as to cause the bonding material to bond the first probe molecules to the first test site by entrapment of the probes in the bonding material which will be cross-linked by the presence of the light.
  • the circuit is then broken by deactivating the light source and the first solution is removed leaving a test site with a plurality of identical probes bound thereto.
  • the fabrication process continues by providing a second solution, containing a plurality of second probe molecules, in electrical contact with the plurality of test sites 30.
  • An electrical potential is applied between the second solution and the layer of electrically conductive material 14 by means of leads 18 and 20.
  • a beam of light 33 is directed through a second portion 34 of the photoconductive layer 16 to complete an electrical circuit between the layer of electrically conductive material 14 and the second solution through the second portion 34 of the photoconductive layer 16 and a second test site 30 of the array of test sites.
  • Completing the electrical circuit causes second probe molecules in the second solution to be attracted to a second test site 30 where they are bound as described above and as described in greater detail below.
  • FIG. 3 illustrated is a specific method of bonding probe molecules 40 to a test site 42 according to the present invention.
  • the method includes providing a substrate 45 having test site 42 defined on a surface thereof.
  • test site 42 defined on a surface thereof.
  • Metal base 47 can be formed in any convention manner such as depositing by small melting metal tip.
  • a beam of light 50 from a light source 52 is directed onto metal base 47 so as to heat metal base 47.
  • a solution 53 includes bonding material 54 coupled to bio-molecules 40. Bonding material 54 melts in response to the heat of metal base 47 and adheres to test site 42 in depression 46 and to metal base 47. Any material which can be bonded to the probe molecules and which will melt at the temperatures generated can be employed.
  • An example of a bonding material is polystyrene which has been chemically modified, as will be understood by those skilled in the art, to perform the bonding or entrapment features.
  • metal base 47 is shown as being conical in shape, other shapes (e.g. single shapes or plurality of shapes which can include cones, blobs, droplets, pads, etc.) are anticipated, with the conical shape providing the largest surface area and providing the most efficient shape for heat conduction.
  • test site 62 is defined by a light source 67 as illustrated by broken lines 68.
  • a beam of light 69 from light source 67 is directed onto test site 62.
  • a solution 70 includes bonding material 72 which crosslinks under the influence of beam of light 69, capturing and retaining probe molecules 60.
  • the bonding material is polyacrylamide.
  • other bonding materials may be employed which cross-link in the presence of light.

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  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Steroid Compounds (AREA)
  • Investigating Or Analyzing Materials Using Thermal Means (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
EP99953162A 1998-10-19 1999-10-14 Verfahren zum fixieren von bio-molekülen an eine probestelle Expired - Lifetime EP1124631B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/174,606 US6096172A (en) 1998-10-19 1998-10-19 Method of bonding bio-molecules to a test site
US174606 1998-10-19
PCT/US1999/023880 WO2000023182A2 (en) 1998-10-19 1999-10-14 Method of bonding bio-molecules to a test site

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EP1124631A2 true EP1124631A2 (de) 2001-08-22
EP1124631B1 EP1124631B1 (de) 2004-07-14

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US (1) US6096172A (de)
EP (1) EP1124631B1 (de)
JP (1) JP3533374B2 (de)
AT (1) ATE270919T1 (de)
DE (1) DE69918708D1 (de)
WO (1) WO2000023182A2 (de)

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DE19962803A1 (de) * 1999-12-23 2001-07-05 Basf Ag Verfahren und Vorrichtung zur maskenfreien Herstellung von Biopolymeren
US6858114B2 (en) 2001-07-03 2005-02-22 The University Of Alabama Laser hydrolysis of polypeptides
EP1409128A2 (de) * 2001-07-17 2004-04-21 Frieder Breitling Verfahren und anordnung zum anbringen von in transportmitteln immobilisierten substanzen sowie monomerpartikel
US20040115336A1 (en) * 2002-12-12 2004-06-17 Industrial Technology Research Institute Method of fabricating a grating-based optical biosensor
AU2003903295A0 (en) 2003-06-30 2003-07-10 Raustech Pty Ltd Substrate for combinatorial chemistry
AU2003903296A0 (en) 2003-06-30 2003-07-10 Raustech Pty Ltd Chemical compositions of matter
DE102004021904B4 (de) * 2004-05-04 2011-08-18 Carl Zeiss Microlmaging GmbH, 07745 Verfahren und Vorrichtung zur Erzeugung einer Analyseanordnung mit diskreten, separaten Messbereichen zur biologischen, biochemischen oder chemischen Analyse
GB201314721D0 (en) 2013-08-16 2013-10-02 Almagen Ltd A method of selectively masking one or more sites on a surface and a method of synthesising an array of molecules

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Also Published As

Publication number Publication date
JP2002527759A (ja) 2002-08-27
US6096172A (en) 2000-08-01
JP3533374B2 (ja) 2004-05-31
WO2000023182A3 (en) 2000-10-12
WO2000023182A2 (en) 2000-04-27
DE69918708D1 (de) 2004-08-19
EP1124631B1 (de) 2004-07-14
ATE270919T1 (de) 2004-07-15

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